Inhibition of 11β-hydroxysteroid dehydrogenase Type 1 (11β-HSD-1), an enzyme that catalyzes regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues, represents a novel approach to the treatment of the conditions associated with the Metabolic Syndrome, including hypertension, obesity, dyslipidemia, and Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Inhibitors of this enzyme may also have utility to treat or prevent age-associated cognitive impairment. The therapeutic potential of inhibitors of 11β-HSD-1 has been reviewed: B. R. Walker and J. R. Seckl, “11β-Hydroxysteroid dehydrogenase Type 1 as a novel therapeutic target in metabolic and neurodegenerative disease,” Expert Opin. Ther. Targets, 7: 771-783 (2003).
U.S. Pat. No. 6,849,636 describes a class of substituted 1,2,4-triazoles, which are potent inhibitors of the 11β-HSD-1 enzyme and therefore useful for the treatment of Type 2 diabetes, hyperglycemia, obesity, dyslipidemia, hypertension, and cognitive impairment. Specifically disclosed in U.S. Pat. No. 6,849,636 is 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole.
However, there is no disclosure in U.S. Pat. No. 6,849,636 of the newly discovered crystalline anhydrate forms of 3-[4-(3-ethanesulfonyl-propyl)-bicyclo[2.2.2]oct-1-yl]-4-methyl-5-(2-trifluoromethyl-phenyl)-4H-1,2,4-triazole of structural formula I below (hereinafter referred to as Compound I).
The present invention also discloses novel crystalline methanol and ethanol solvates of Compound I.